The process of development of an API (Active Pharmaceutical Ingredient) into the marketed dosage form can be challenging and time and resources consuming. This can often be attributed to limitations in terms of solubility, stability, bioavailability and processability into different dosage forms. Such limitations can be addressed by manipulating their solid form through a variety of formulation techniques including particle size and shape, solid phase, ionic (i.e. salt formation) and neutral (i.e. cocrystallisation) complexing to achieve the goal of improving their physicochemical characteristics and ultimately their pharmaceutical profile.
A pharmaceutical cocrystal is a form where a second molecule (usually called a guest molecule or coformer) is hydrogen bonded to the active substance to create an alternative form of the active substance with different physicochemical properties. It can be prepared by different methods including solvent crystallisation where both active substance and crystal former is dissolved in a single or mixture solvent system or each is dissolved separately and the solutions mixed to form the final solution that produce the cocrystal after solvent removal or phase separation. The cocrystal may then precipitate or crystallise as the solvent mixture is evaporated slowly. This process has also been automated to a high throughput screening system (see US2005/0267209).
Cocrystals have also been prepared by other methods including:
1. Crystallisation from the melt: A cocrystal may be obtained by melting the cocrystal components together and allowing recrystallisation to occur. In some cases, an anti-solvent may be added to facilitate crystallisation.
2. Thermal microscopy: A cocrystal may be obtained by melting the higher melting component on a glass slide and allowing it to recrystallise. The second component is then melted and is also allowed to recrystallise. The cocrystal may form as a separated phase/band in between the eutectic bands of the original components.
3. Mixing and/or grinding: A cocrystal may be obtained by mixing or grinding two or more components together in the solid state.
4. Solvent drop grinding: A cocrystal may be obtained by adding a small amount of organic solvents to a grinding of the components. (see Shan, N., Toda, F., Jones, W. Chem. Commun., 2002, 2372-2373).
Supercritical fluids (SCFs) have been used for extraction and fractionation of natural products such as decaffeination of coffee, extraction of essential oils from hop and spices. It's also been used in chromatography as mobile phases, medium for chemical reactions, dyeing of textiles and for particle formation. There are a large number of publications in the public domain where supercritical fluids in particular carbon dioxide has been used to control particle sizes and morphologies of sensitive materials such as pharmaceuticals (see WO 95/01221 and WO 99/59710, and U.S. Pat. No. 6,620,351) and been employed to perform polymorph screening of pharmaceuticals (see WO 2005/105293). The use of supercritical carbon dioxide in pharmaceutical processing is further described in Subramaniam et al., J. Pharm. Sci. 1997: 86, 8.
The scope for the work in active particle formation from SCFs was generally directed towards particle engineering and design of pure active substances or active substance and polymer system for controlled/sustained release of the API. In addition, the person skilled in the art would expect that particle formation of more than one pure, crystalline component/material of interest in a single solid structure to be problematic due to molecular incompatibility amongst other reasons that discourage nucleation and growth of both components in a single crystalline structure when the solvent system is removed rapidly by the SCF and more specifically when the SCF is used as anti-solvent and rapid deposition of crystals results. The molecular interactions between the solvent and pure components can greatly differ so as their nucleation and growth rates thus raising the likelihood of forming a physical mix of both pure compounds. Even if the product produced by supercritical fluid techniques (e.g. SEDS, SAS and SAS EM) looks uniform on physical examination or by certain solid state characterisation (e.g. SEM, particle size analysis), it is expected that PXRD analysis would show a profile of a mixture of both pure components, not an altogether different profile as the case tend to be with cocrystals. It is also expected that pure compounds could crystallise on top of each other due to the rapid solvent removal by the SCF, subsequent increase in solution super saturation and subsequent nucleation and growth.